Novel SCN4A Variants Associated With Myalgic Myotonic Disorder or Paramyotonia

Area of Science:

• Genetics
• Neurology
• Molecular Biology

Background:

• Investigated five novel SCN4A variants potentially linked to paramyotonia or myotonic disorders.
• Examined ten patients across seven families with suspected hereditary muscle conditions.

Purpose of the Study:

• To determine the pathogenicity and functional impact of five new SCN4A variants.
• To expand the understanding of SCN4A-related myopathies.

Main Methods:

• Clinical, neurophysiological, imaging, and muscle biopsy assessments.
• Targeted gene sequencing for myopathy-related genes.
• Functional analysis of variants using HEK293T cells and whole-cell patch clamp electrophysiology.

Main Results:

• Identified five SCN4A variants: p.(F221S), p.(A715T), p.(R1451H), p.(N1204D), and p.(F1419L).
• Patients presented with exercise/cold-induced myalgia, stiffness, cramping, and variable weakness.
• Four variants demonstrated gain-of-function effects, while N1204D did not show association with myotonia.

Conclusions:

• All five SCN4A variants are likely pathogenic, with N1204D being an exception regarding myotonia.
• These findings broaden the spectrum of SCN4A mutations.
• Consider these variants in patients with paramyotonia or exercise-induced myalgia/cramping with EMG-confirmed myotonia.